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Lipiodol in Lymphography—From Diagnostics to Theranostics

Pieper, Claus Christian MD*; Hur, Saebeom MD; Sommer, Christof-Matthias MD‡,§; Nadolski, Gregory MD; Maleux, Geert MD; Kim, Jinoo MD, PhD#; Itkin, Maxim MD

doi: 10.1097/RLI.0000000000000578
Review Article
Free
SDC

Lipiodol is an iodinated poppy seed oil first synthesized in 1901. Originally developed for therapeutic purposes, it has mainly become a diagnostic contrast medium since the 1920s. At the end of the 20th century, Lipiodol underwent a transition back to a therapeutic agent, as exemplified by its increasing use in lymphangiography and lymphatic interventions. Nowadays, indications for lymphangiography include chylothorax, chylous ascites, chyluria, and peripheral lymphatic fistula or lymphoceles. In these indications, Lipiodol alone has a therapeutic effect with clinical success in 51% to 100% of cases. The 2 main access sites to the lymphatic system for lymphangiography are cannulation of lymphatic vessels in the foot (transpedal) and direct puncture of (mainly inguinal) lymph nodes (transnodal). In case of failure of lymphangiography alone to occlude the leaking lymphatic vessel as well as in indications such as protein-losing enteropathy, postoperative hepatic lymphorrhea, or plastic bronchitis, lymphatic vessels can also be embolized directly by injecting a mixture of Lipiodol and surgical glues (most commonly in thoracic duct embolization). The aim of this article is to review the historical role of Lipiodol and the evolution of its clinical application in lymphangiography over time until the current state-of-the-art lymphatic imaging techniques and interventions.

From the *Department of Radiology, University Hospital Bonn, Bonn, Germany

Department of Radiology, Seoul National University Hospital, Seoul, Republic of Korea

Clinic for Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg

§Stuttgart Clinics, Stuttgart, Germany

Division of Interventional Radiology, Department of Radiology, University of Pennsylvania, Philadelphia, PA

Department of Radiology, University Hospitals Leuven, Leuven, Belgium

#Department of Radiology, School of Medicine, Ajou University Hospital, Suwon, Republic of Korea.

Received for publication February 18, 2019; and accepted for publication, after revision, April 2, 2019.

Conflicts of interest and sources of funding: C.C.P. is part of the speakers bureau of and/or received educational grants from Philips Healthcare, Bayer Vital, Boston Scientific, Guerbet, and Medserena; G.M. and C.M.S. are both part of the speakers bureau at Guerbet; M.I. is part of the speakers bureau at and received research grants from Guerbet.

Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.investigativeradiology.com).

Correspondence to: Claus Christian Pieper, MD, Department of Radiology, University Hospital Bonn, Sigmund-Freud Strasse 25, 53127 Bonn, Germany. E-mail: claus.christian.pieper@ukbonn.de; pieper.lymphatic@gmail.com.

Online date: July 8, 2019

The end of the 19th century was the heyday of lymphatic research, and enormous amounts of basic scientific knowledge were generated. However, it was practically forgotten over the last half of century. The primary reason for that was the inability to transfer this knowledge into clinical practice due to absence of robust means to evaluate the status of the lymphatic system in clinical settings. The only option to gain information in vivo about the lymphatic system was by conventional oily lymphangiography, nowadays an almost forgotten technique since the introduction of cross-sectional imaging. Conventional lymphangiography is closely linked to the availability of Lipiodol (Guerbet, Roissy, France).

Lipiodol, originally developed in 1901 for therapeutic purposes, has mainly become a diagnostic contrast medium since the 1920s. However, it took until the end of the 20th century for interventional therapeutic options based on opacification of the lymphatic system by Lipiodol to be developed. The aim of this article is to review the historical role of Lipiodol and the evolution of its clinical application in lymphangiography over time until the current state-of-the-art lymphatic imaging techniques and interventions.

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LIPIODOL

Lipiodol is a pale yellow to amber, clear liquid, oily contrast medium widely used in interventional procedures. Lipiodol is marketed by Guerbet (Roissy, France) as a solution for injection in 10-mL glass ampoules using the brand name Lipiodol Ultra Fluid. In literature, Lipiodol is regularly mentioned as iodized or ethiodized oil. Until 2012, Lipiodol was called “Ethiodol” in the United States.

Lipiodol is a mixture of long-chain (C16 and C18) di-iodinated ethyl esters of fatty acids of poppy seed (Papaver somniferum var. nigrum) oil. It contains 98% unsaturated fatty acids with linoleic acid as the predominant fatty acid (70%).1 Lipiodol contains 37% (wt/wt) iodine (ie, an iodine concentration of 480 mg/mL). The viscosity of Lipiodol at 37°C is approximately 25 mPa·s (and 50 mPa·s at 20°C), and its density is 1.28 g/cm3.2,3

Lipiodol is known to corrode specific types of plastic, for example, polystyrene. Therefore, glass syringes or specially tested materials should be used for application of Lipiodol. The syringe-tube-needle system used for injection should always be checked for compatibility before intervention (Fig. 1).

FIGURE 1

FIGURE 1

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HISTORY OF LIPIODOL

Lipiodol was first synthesized by the French pharmacist Marcel Guerbet (1861–1938) in early 1901 in the Paris School of Pharmacy Chemistry Laboratory. In May 1901, Lipiodol was presented for the first time by his colleague Laurent Lafay at the French Society of Dermatology and Syphilography.4 Lipiodol was originally marketed for therapeutic applications in syphilis, pulmonary (asthma) and cardiovascular diseases (angina, pericarditis), impetigo, and rheumatism.5 In 1921, the radiologists Jean-Athanase Sicard and Jacques Forestier discovered its x-ray opacifying properties. On October 13, 1921, the first myelography was performed in a patient with paralysis, probably caused by a spinal cord tumor.6 No adverse effects were observed after epidural injection of Lipiodol. Moreover, Lipiodol did not remain at the injection site and travelled along the spinal canal as shown by x-ray imaging performed several days after the procedure.

Other radiological applications for Lipiodol were developed afterwards: bronchography in 1922, dacryography in 1923, hysterosalpingography in 1924, sialography and fistulography in 1928, as well as urethrography and cystography.5 Lymphangiography was first described as a clinical technique by Kinmonth in 1952.7 Up to this point, diagnostic radiological indications outnumbered therapeutic indications for Lipiodol use. A remarkable exception was the use of Lipiodol as a long-lasting source of iodide1,8 in the prophylaxis and treatment of endemic goiter.9

It took several decades for additional therapeutic indications for Lipiodol to be established leading to a transition from diagnostic to therapeutic applications of Lipiodol. Nowadays, Lipiodol is most commonly used for mixing with N-butyl cyanoacrylate (NBCA)–based glues for vessel embolization or in cancer treatment in combination with cytotoxic drugs, exemplified by conventional transarterial chemoembolization (cTACE). Two randomized controlled trials in 2002 and one meta-analysis in 2003 showed survival benefit of cTACE over best supportive care for the treatment of hepatocellular carcinoma (HCC).10–12 These studies established cTACE as a standard of care for intermediate stage HCC patients in the European Association for the Study of the Liver guidelines.13

Despite the fact that lymphangiography is an authorized indication for Lipiodol use, Lipiodol is mainly used for other indications: for the treatment of HCC by cTACE,14 for the treatment of acute arterial bleeding,15 as well as for cerebral or peripheral arteriovenous malformations by mixing Lipiodol with NBCA-based glues.16,17 The use of Lipiodol for tubal flushing during hysterosalpingography examination has recently been proposed for the management and fertility enhancement of unexplained infertility in women.18,19

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THE LYMPHATIC SYSTEM

The anatomy of the lymphatic system closely parallels that of the peripheral vascular system. Its basic function is returning interstitial fluid (termed lymphatic fluid after entering the lymphatic vessels) to the vascular system. There are 3 distinct lymphatic systems that are different in function and fluid composition: liver, intestinal, and soft tissue lymphatic systems. All of these systems drain into the cisterna chyli (located in the retroperitoneum at the level of thoracic verteba 12 to lumbar vertebra 2). From here, the lymphatic fluid is drained via the thoracic duct—the largest lymphatic vessel of the human body—into the left venous angle, Supplementary Figure 1, Supplemental Digital Content 3, http://links.lww.com/RLI/A462. Anatomical variations of the lymphatic system are common.20 The second major lymphatic vessel of the body is the right lymphatic duct. It drains most of the right upper quadrant of the body, whereas the thoracic duct drains the lower body including the extremities and abdomen. Overall, approximately 80% of the lymphatic fluid flowing within the thoracic duct is generated by the liver and intestinal lymphatic system.21 Once the lipid/chylomicron-rich and protein-rich fluid from the liver and intestine is mixed with the lymph of lower part of the body, the resulting fluid is called chyle.

The key functions of the lymphatics include the defense against foreign particles and microorganisms, restoration of any excess protein molecules and interstitial fluid back to the systemic circulation, and absorption of fat-soluble vitamins and fatty substances from the gastrointestinal tract and to transport them to the venous circulation.22 Without active removal of the proteins from the interstitial tissue by the lymphatic system, accumulation of the proteins in the interstitial tissue would result in progressive interstitial edema.

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HISTORY OF LYMPHOGRAPHY

At the end of the 19th century, the physiologist Ernest H. Starling described the mechanism of movement of fluid from vessels into the interstitial tissues, as a first step in creation of the lymph in the body.23,24 Visualization of the lymphatic system was crucial for further research and clinical applications. Several techniques with contrast injection into lymph nodes (LNs) or body cavities were investigated with visualization of only limited segments of the lymphatic system. In the 1960s, the use of Lipiodol was established in lymphography as it is retained in the lymphatic system as opposed to iodinated hydrosoluble contrast media, which diffuses out of the lymphatics rather quickly. Before the development of cross-sectional imaging, lymphography was used for the evaluation of LNs (so-called lymphadenography), especially in patients with lymphoma or suspected LN metastases.

Recently, dynamic contrast-enhanced magnetic resonance lymphangiography (DCE-MRL) and transpedal contrast-enhanced magnetic resonance lymphangiography as new imaging modalities of the lymphatic system have been developed (note: MRL is an off-lable use of MR contrast media).25,26 Both techniques utilize dynamic magnetic resonance imaging during injection of a nonspecific gadolinium-based contrast agent into the LNs in the groin or into the cutis of the foot. Magnetic resonance lymphangiography has been found to be of significant value for diagnosis and treatment of patients with thoracic lymphatic disorder, forgoing the problems of an oily contrast agent.

Nowadays, the field of Lipiodol applications within the lymphatic system includes diagnostic lymphangiography as well as lymphangiography-guided lymphatic interventions, which will be reviewed in detail in the following sections.

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CONTEMPORARY INDICATIONS OF LYMPHANGIOGRAPHY

Lymphangiography today is a standard technique in the management of iatrogenic and idiopathic lymphatic leakage in different locations (Table 1). Chylothorax, chylous ascites, chyluria, and lymphatic fistula/lymphocele in the neck, pelvis, and groin/lower extremity define the majority of indications for lymphangiography in the broad field of therapy refractory postoperative lymphatic fistula.27–33 Lymphangiography for idiopathic lymphatic leakage is performed markedly less frequent in the clinical routine. Irrespective of the nature of lymphatic leakage, the drainage volume can vary significantly (between a few deciliters and a few liters per day) and can be regarded as a marker of clinical severity of the underlying disease.29,30,32,34 Especially patients with central high-output lymphatic leakage are at risk of death due to malnutrition and immunodeficiency.35 Low-output lymphatic leakage, which can be observed regularly after surgery in the neck and groin/lower extremity, significantly prolongs wound healing and bears the risk of complicating superinfection.35 All patients with lymphatic leakage experience a decreased quality of life and prolonged in- and out-patient care.35

TABLE 1

TABLE 1

There are 2 main access sites for introduction of contrast agent into the lymphatic system, Supplementary Figure 2, Supplemental Digital Content 4, http://links.lww.com/RLI/A463:

  1. transpedal lymphangiography (TL) via cannulation of a lymphatic vessel in the foot, and
  2. transnodal lymphangiography via direct puncture of an LN.

Both techniques have specific advantages and disadvantages, so that the adequate access site has to be chosen according to the clinical indication as well as to practitioner's preference.

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TRANSPEDAL LYMPHANGIOGRAPHY

Transpedal lymphangiography is a method for selective visualization of the lymphatic system with application of Lipiodol via a transpedal access. After intradermal injection of a blue dye (initial solution: 100-mg Patent Blue V [Guerbet, Roissy, France; 4 mL] and 4 mL Xylocaine 1% [lidocaine; AstraZeneca, London, United Kingdom]) into the first, second, and third interdigital space (1–3 mL blue dye per interdigital space), superficial lymph ducts at the arch of the foot can be identified macroscopically (Fig. 2A), dissected selectively under local anesthesia and punctured with a 21- to 25-gauge cannula (Fig. 2B). Via this ultraselective lymphatic access, Lipiodol can be injected (recommended maximum volume of 20 mL; maximum injection speed of 30 mL/h for transpedal application; Video 1, Supplemental Digital Content 1, http://links.lww.com/RLI/A438, video demonstrating contrast injection with a 1-mL syringe for TL [maximum volume of 20 mL and maximum injection speed of 30 mL/h]) and timely visualized applying fluoroscopy and radiography (Fig. 3, A and B).28,36 During and at different time points after Lipiodol injection, dependent on the intake capacity of the lymphatic system, fluoroscopy, radiography, and computed tomography (CT) can be used to visualize the lymphatic system selectively (LNs and small and large lymph ducts).30,37 In addition, TL in combination with x-ray imaging allows visualization of different lymphatic pathologies such as lymphatic fistula, lymphoceles, chylous ascites, chyluria, and chylothorax. In this context, the importance of adequate timing for and technique of x-ray imaging has to be emphasized. Despite rather high interindividual variability, there are reference numbers for the duration of Lipiodol propagation into the different regions of interest after transpedal application and, consequently, for the adequate timing of x-ray imaging in the filling phase: 0 to 0.5 hour after Lipiodol application for the lower extremity and groin,30,38 0.5 to 3 hours after Lipiodol application for pelvis and abdomen,32,35,38,39 and 1 to 26 hours after Lipiodol application for thorax and neck.28,30,33,39–41 In multiple studies and irrespective of the underlying pathology, x-ray imaging in the nodal phase is performed regularly 24 hours after Lipiodol application.27,29,31,39,42

FIGURE 2

FIGURE 2

FIGURE 3

FIGURE 3

Fluoroscopy and radiography are the standard imaging modalities to visualize the Lipiodol propagation. However, for making the imaging diagnosis of the underlying pathology in a specific region of interest, CT (CT lymphangiography) is often superior to fluoroscopy/radiography for the exact definition of type and extent of lymphatic pathology.43–46

Although there is no standardization of terminology, different articles define imaging criteria for different types of lymphatic pathologies on the basis of x-ray imaging. Indirect signs of lymphatic leakage, irrespective of its localization, is pathological Lipiodol extravasation as it is described in multiple TL studies,28,31–33,37,39–41,43,47–51 and Lipiodol pooling as it is mentioned in one TL study.39 During and after TL, there is a variety of indirect signs of lymphatic leakage that can vary dependent on the location: pathological Lipiodol pooling,32,38,40,51,52 lack of Lipiodol in the centripetal part of the thoracic duct,48 pathological disruption of the centripetal Lipiodol distribution,31 atypical opacification of the lymphatic ducts as a sign of lymphatic collateralization,31 as well as Lipiodol detection in the drainage reservoir31 (Fig. 4).

FIGURE 4

FIGURE 4

Our clinical experience has shown, however, that further indirect signs of lymphatic leakage can be defined: opacification of a lympho-pseudoaneurysm and retrograde (centrifugal) opacification of the lymphatic system (eg, the contralateral pelvis, the mesentery, the liver hilum, the kidney, the bronchovascular bundle or lung [Fig. 5], and the axilla), usually termed lymphatic reflux. Deso et al37 published about the unparalleled abilities of fluoroscopy/radiography as the imaging modalities for TL and emphasized the added benefit of CT lymphangiography in the diagnosis and fine anatomic localization of lymphatic leakage. In the analyzed cohort with patients experiencing different types and locations of lymphatic leakage, initial fluoroscopy/radiography alone or CT lymphangiography localized the lymphatic leakage in 25% and 37.5%, respectively.37 In the other 37.5%, both imaging modalities were equal in terms of localizing of the lymphatic leakage.37 Furthermore, CT lymphangiography is crucial for the detailed visualization of the Lipiodol in the healthy lymphatic system proximal and distal to the pathology (afferent and efferent system) and identification of relevant anatomical structures such as arteries and veins are extremely important for the specific planning of potential lymphatic second-line interventions (such as percutaneous ethanol sclerotherapy of afferent lymph ducts, interstitial glue embolization via LNs, and percutaneous puncture of the cisterna chyli with subsequent catheterization and glue embolization of the thoracic duct).23,30,53–55 In regard to CT lymphangiography acquisition technique, different advantages and disadvantages can be discussed. Advantages include the high spatial resolution of imaging and the relatively broad temporal window for the acquisition of “static” images (in this light, CT lymphangiography can be implemented easily in the clinical routine work flow). In contrast to DCE-MRL, CT lymphangiography does not allow for the acquisition of high-resolution temporal images with documentation of the dynamic distribution of the contrast material within the lymphatic system. For the future, it can be expected that the use of modern CT image acquisition (eg, dual-energy CT) and reconstruction (eg, multiplanar image reconstruction) technologies further increase the detection rate of lymphatic pathology due to optimized and selective visualization of Lipiodol. In this context, Lipiodol as the only contrast medium with a European and a Food and Drug Administration approval for lymphangiography is essential.

FIGURE 5

FIGURE 5

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TRANSNODAL LYMPHANGIOGRAPHY

Intranodal lymphangiography offers an alternative means of accessing the lymphatic system. This technique has been described for the use in thoracic duct embolization (TDE) and MRL, offering a less technically challenging alternative to the conventional pedal lymphangiography.56 Using ultrasound- or fluoroscopy-guided puncture of LNs with a 25-gauge needle or similar-sized angiocatheter, this procedure uses fundamental skills and equipment available to all interventional radiologists.57 A portion of the injected Lipiodol is retained within the LNs, while another portion is transported with the venous circulation into small peripheral pulmonary arteries where it is retained. Possible ensuing severe complications such as pulmonary failure or cerebral embolization of the Lipiodol (via an unrecognized right-to-left shunt) have been described but are very rare.23,58 Over the course of several days and weeks, the iodine within the Lipiodol is released by enzymatic cleavage and the fat molecules are degraded (comparable to other fats presumably by β-oxidization).1,59 Especially in cases of larger Lipiodol collections, this process may take several months.58

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ULTRASOUND-GUIDED INGUINAL LYMPH NODE ACCESS

Under real-time ultrasound guidance, the bilateral inguinal LNs are accessed with a 25-gauge spinal needle (BD, Franklin Lakes, NJ) preassembled with a short piece of extension tubing connected to a syringe with Lipiodol to minimize needle movement. The preassembled needle configuration consists of the following components: 25-gauge spinal needle with stylet removed attached to a 3-mL polycarbonate syringe (Merit Medical, South Jordan, UT) using a short extension tubing used for an intravenous angiocatheter and flushed with Lipiodol. The needle tip is positioned in the transitional zone between the cortex and hilum of the LN using a shallow angle to create a relatively long subcutaneous tract to assist in stabilizing the needle (Fig. 6). The external portion of the needle is secured using adhesive tape or a see-through dressing. Under fluoroscopic guidance, Lipiodol is injected by hand at a rate of approximately 0.1 mL/min.

FIGURE 6

FIGURE 6

An alternative method to confirm intranodal placement of the lymphangiogram needle is to use contrast-enhanced ultrasound.60 The injection of ultrasound contrast into the lymphatics is an off-label use of ultrasound contrast. However, the initial experience with this technique in 28 patients did not report any serious adverse events related to injection. This technique is particularly useful for confirming intranodal needle placement for DCE-MRL because it eliminates the need for fluoroscopy equipment near the magnetic resonance scanner and reduces the number of patient transfers after needle placement, which can dislodge the needle from the node. In this technique, the position of the needles in the LNs and efferent lymphatic flow is confirmed by injecting 1 mL of the ultrasound contrast agent (Lumason; Bracco, Monroe Township, NJ) mixed with 2 mL of lidocaine and observing contrast enhancement of the efferent lymphatic ducts leading to the pelvis from the LN. Venous intravasation of ultrasound contrast can also be detected using this technique. If either subcutaneous extravasation or venous intravasation is identified, the ultrasound can be returned to gray scale imaging, the needle repositioned, and additional contrast injected to confirm proper lymphatic flow of contrast.

Once an efferent lymphatic vessel and/or LN is identified to confirm proper positioning of the needle by either method, conventional lymphangiography can be performed by further injection of Lipiodol using an angioplasty balloon inflator filled with 10 mL of Lipiodol. The inflator is tightened to administer the contrast using a pressure of approximately 3 atm to propagate the contrast into the lymphatic system at a relatively constant rate similar to the lymphatic pumps used in pedal lymphangiography. A total volume of approximately 6 to 12 mL of Lipiodol can be injected into each LN.

For TDE, infusion of contrast can be terminated once the contrast opacifies the lymphatics at approximately the L3 level as this is the typical location of the largest abdominal lymphatics leading into the cisterna chyli or once a total of 20 mL of Lipiodol has been infused into the LNs. If at the end of the contrast injection the cisterna chyli or upper abdominal lymphatic for access have not been imaged, the contrast bolus can be flushed forward by injecting normal saline using 10-mL syringes at a rate of 10 mL per 1 minute to propagate the contrast forward.58,61 The injection of saline into the LNs may be perceived as painful even in a patient under moderate sedation and can be preceded by injection of 1 mL of 1% lidocaine to anesthetize the node. In addition, sequential pneumatic compression devices can be placed on the calves of the patient before initiating the lymphangiogram to reduce lymphatic transit time by approximately 20 minutes on average.

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FLUOROSCOPY-GUIDED ILIAC LYMPH NODE ACCESS

Because LNs and lymphatic vessels cannot be discerned from surrounding tissues on fluoroscopic images, pure fluoroscopy-guided LN access is not possible. However, it may be attempted when the ultrasound-guided inguinal LN puncture and Lipiodol injection were done without achieving a suitable lymphangiography, because even in these cases a small amount of Lipiodol might stain iliac LN. Fluoroscopy provides very high spatial and temporal resolution, enabling precise needle guidance. Thus, even in patients where ultrasound-guided inguinal lymphangiography was difficult due to small and fragile inguinal LNs, contrast media including Lipiodol can be injected at a faster rate through the iliac LNs after being punctured under fluoroscopy.

For preparation, the LN should be placed in the center of the anterior-posterior projection screen. The skin over the target iliac LNs stained by Lipiodol should be prepared for the following aseptic procedures and then local anesthesia is done. By placing a metal object on the anesthesia area, the skin entry point can be marked on the fluoroscopic image. Afterward, rotate the C-arm up to 90 degrees to measure the distance from the skin entry point to the target LN in the lateral projection to select a needle with proper length. To prevent the needle from moving after the puncture, the needle should be connected to a syringe that is loaded with contrast medium via flexible connecting tube in advance.

To puncture the LN, the needle should be vertically advanced toward the target LN based on the anterior-posterior projection of the fluoroscopic image, which is corresponding to the bull's-eye view. It is recommended that the needle is operated with a needle holder to avoid radiation exposure to operator's hand. The remaining distance to the target should be checked on the lateral projection from time to time. One can perceive the needle has approached the LN by observing the target LN moving along when the needle is pushed or shaken (Fig. 7).

FIGURE 7

FIGURE 7

If the needle is judged to have reached the desired portion of the LN, gentle pressure should be applied to the syringe to start injecting contrast medium. It may be more difficult to tell early, whether the injected contrast medium is leaking or entering into the lymphatic system. The LNs have already been stained by Lipiodol in the fluoroscopy-guided access. If the leakage is clear based on its appearance or efferent lymphatic vessels do not appear despite contrast injection, the puncture can be judged to be unsuitable. If this is the case, the needle can be repositioned to other areas within the capsule before complete retreat.

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FLUOROSCOPY-GUIDED ACCESS OF PARA-AORTIC OR OTHER DEEPLY SEATED LYMPH NODES

The same technique can be applied to the access of more deeply seated LNs such as para-aortic or other abdominal LNs, which cannot be guided by ultrasound. As described previously, a needle with appropriate length to reach the target should be chosen based on the lateral projection. If there are structures on the vertical path that must be avoided, C-arm CT and its specialized guidance programs will be helpful for planning the path of the needle. The longer the path is, the more delicate control of the needle is required, and sometimes it cannot be achieved with a needle holder and a straight needle. In these situations, a rotating bended needle technique can give the operator better control of needle direction. Before sticking the needle, its end can be bent slightly. Then, the needle is advanced with one hand while its direction is being controlled by rotating the needle hub with the other hand. During this maneuver, lead gloves are recommended (Fig. 8).

FIGURE 8

FIGURE 8

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INTRAOPERATIVE ULTRASOUND-GUIDED MESENTERIC LYMPH NODES ACCESS

Chylous lymphatic fluid solely formed in the small bowel travels through the mesenteric lymphatic system to join the cisterna chyli via its mesenteric trunk. Because contrast medium injected through inguinal or retroperitoneal LNs usually does not move against the flow direction of the chylous lymphatic fluid, the mesenteric trunk and its upstream mesenteric lymphatic system is rarely visualized in any lymphatic examination. In patients with chylous ascites without detection of a leakage site by conventional lymphangiography, many times open surgery is indicated to identify and close the leakage site. Unfortunately, mesenteric lymphatic leakages are difficult to identify even by surgical approach. Mesenteric LN lymphangiography offers opacification of the upstream mesenteric chylous lymphatic system and can detect the mesenteric lymphatic leakage. Exploratory laparotomy is required for this purpose. Mesenteric LNs can be punctured using a 26-gauge needle under ultrasound guidance with the high-frequency linear probe (8–15 MHz) of a portable ultrasound system as in standard inguinal LN access62 (Fig. 9). If a mesenteric lymphatic leakage site is detected by this approach, it can be embolized or surgically treated afterward.

FIGURE 9

FIGURE 9

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THERAPEUTIC EFFECT OF LYMPHANGIOGRAPHY

In a substantial number of patients with lymphatic leakage, single or repetitive lymphangiography alone is therapeutic. Due to Lipiodol-induced selective blockage of the pathological lymph ducts and sterile inflammatory reactions leading to scarring, the lymphatic leakage can undergo healing within a few days or weeks.63 According to a systematic review (submitted for publication) including 7 original case series with a total of 195 patients, the clinical success rate of TL is 51% to 100%.27,29,31,32,35,38,39,64 The included patients presented with a lymphatic leakage volume of 10 to 3700 mL/d at the day of TL resulting from chylothorax, chylous ascites, and thoracic, abdominal, and peripheral lymphatic fistula/lymphocele. After TL, healing of the lymphatic leakage occurred within 2 to 31 days. It is important to note, that clinically successful treatment of lymphatic leakages by lymphangiography alone vastly depends on the drainage volume with lower success rates in high-output fistulas.

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LYMPHATIC INTERVENTIONS

There was a dramatic increase of possible lymphatic interventional procedures in recent years. All of which follow 2 basic concepts of lymphatic embolization for the treatment of lymphatic leakage or reflux:

  1. intravascular embolization using coils and/or glue via cannulation of a lymphatic vessel (eg, cisterna chyli or thoracic duct for TDE), and
  2. interstitial glue embolization via a LN access.

Depending on the clinical presentation of the patient, a lymphatic intervention can be planned as a primary approach or secondary after initial (but clinically unsuccessful) lymphangiography. Especially in cases with primary lymphatic interventions, MRL is a valuable tool for treatment planning.25,26

In cases with clinical failure after lymphangiography, lymphatic second-line interventions can be planned specifically on the basis of previous CT lymphangiography with identification of the target region.

For most lymphatic interventions, Lipiodol plays a key role not only as a contrast material, but also because the non-x-ray-visible embolization material “glue” is mixed with Lipiodol with the intention to better control polymerization time and lesion targeting65 either under fluoroscopy/radiography (real-time visualization of distribution of the Lipiodol/glue mixture during injection to avoid complications such as transvenous passage) or under CT (after embolization to document the adequate embolization end point with embolization of all relevant lymphatic structures to cure the lymphatic leakage).

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INGUINAL AND ILIAC LN GLUE EMBOLIZATION FOR POSTOPERATIVE PELVIC LYMPHOCELES

Postoperative lymphoceles in the pelvis commonly result from extensive LN dissection during gynecologic or prostatic surgery.64,66,67 The exact prevalence of lymphoceles developing after surgery is unknown because most are known to spontaneously regress over time, and those that remain are usually asymptomatic. However, up to 5% of lymphoceles are known to cause clinical problems, ranging from abdominal distension to secondary infection.68,69 Such cysts are generally indicated for percutaneous decompression by means of drainage catheter insertion. However, owing to persistent inflow of lymphatic fluid from the disrupted lymphatic system, the effect of simple drainage may only be transient and may be followed by immediate re-expansion of the lymphocele.64,69 To prevent this from occurring, sclerotherapy is widely performed which, according to the literature, results in successful outcome between 79% and 94% of treated lymphoceles.64,70,71 The variability in the reported outcome may derive from heterogeneity in the size of the lesions treated, extent of LN dissection, and technical variables including the type and amount of sclerosing agent used. Generally, large-volume (or high-output) lymphoceles are prone to failure, and it was for such clinical scenarios that the idea to embolize the lymphatic inflow supplying the lymphocele was sought.72,73 A report by Shih et al73 supports this idea where the authors described surgical ligation of an inflow lymphatic duct draining into a lymphocele that failed to respond to sclerotherapy.

The field of lymphatic intervention has taken a big stride since the development of intranodal lymphangiography (INL) through LNs in the groin.37,58,74 Once Lipiodol enters the lymphatic channel during transnodal injection, it ascends though the pelvic lymphatic system during which process multiple nodal stations are opacified along the iliac chain. Due to the proximity of these nodal stations to the groin, the leakage points in the pelvis are usually identified within a few minutes of initiating the lymphangiogram.75 The amount of Lipiodol required to opacify leaks is generally much less than that required for other lymphatic procedures. Simultaneous cystography of the lymphocele by injecting iodinated hydrosoluble contrast medium through the drainage catheter helps to outline the location of the lymphocele and allows anatomic association with the leakage point. In a typical scenario, oil drops are seen to extravasate from the disrupted lymphatic channels (or cut-surface of the LNs) and float away into the fluid-filled lymphocele cavity. Although oil-based lymphangiography alone has been demonstrated to have therapeutic effect for lymphatic leaks in various regions of the body, including the thorax and abdomen, there is a lack of therapeutic effect for leaks in the pelvis possibly because the oil escapes freely from the leaking channel into the dead space within the lymphocele cavity.75 Such limitations of lymphangiography may be overcome by percutaneous embolization of inflow lymphatic channels using NBCA-based glues.

The idea behind the endolymphatic approach is to create a polymerized glue cast within the disrupted lymphatic channel, ultimately cutting off the inflow of lymphatic fluid into the lymphocele. The glue can either be directly injected in an antegrade fashion after puncturing an upstream lymphatic channel or LN with a fine needle (Fig. 10) or in a retrograde manner after selective catheterization of lymphatic inflow through the lymphocele cavity using a coaxial microcatheter. The NBCA-based glue is diluted with Lipiodol to prevent early polymerization within the catheter or proximal to the leakage site. The glue-to-Lipiodol ratio is determined according to discretion of the operator depending on the individual anatomy of the patient. When deemed necessary, lidocaine hydrochloride 1% may be injected into the LN when performing upstream intranodal embolization to alleviate pain. In this case, lidocaine should be flushed out with 5% dextrose in water before injecting the glue mixture to avoid premature polymerization.

FIGURE 10

FIGURE 10

The application of embolization for treatment of pelvic lymphoceles is still in its infancy, and therefore, there is a paucity of data on the subject. Furthermore, the literature is limited to case reports and small-sample, retrospective cohorts through which definitive conclusions cannot be reached.29,53,75–77 However, reports so far have been consistent in demonstrating the potential of lymphatic embolization for lymphoceles, in particular as an alternative bail-out measure for lesions that are refractory to sclerotherapy. Initial treatment failure may occur on occasions owing to the presence of multiple leaking channels. In such cases, embolization may be repeated more than once to impede collateral inflow into the lymphocele. Sclerotherapy may also be performed simultaneously in adjunct to lymphatic embolization to enhance the treatment effect. One potential advantage of embolization over sclerotherapy is that embolization is not contraindicated for immature or ruptured lymphoceles that freely communicate with the peritoneal space. Needless to say, more studies are mandatory in the future to strengthen the role of lymphatic embolization for lymphoceles and for the procedure to gain widespread acceptance. As a step forward, a prospective, randomized, double-arm, multicenter trial comparing the efficacy of lymphatic embolization to that of sclerotherapy for the treatment of symptomatic lymphoceles has been initiated and is currently enrolling subjects, aiming to reach sample sizes of 44 subjects per arm over a period of 2 years (LESPOL trial, https://cris.nih.go.kr/cris/mobile/mobile_view_en.jsp?btype=&seq=11944).

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CHYLOTHORAX AND THORACIC DUCT EMBOLIZATION

A chylothorax is a collection of chylous fluid in the pleural cavity due to leakage from lymphatic vessels. Nowadays, the most common causes are surgery (especially esophagectomy/heart surgery) or trauma. However, there are also multiple possible nontraumatic causes of chylothorax, such as erosion or outflow obstruction of a lymphatic vessel by a tumor, primary diseases of the lymphatic vessels (eg, Gorham disease, lymphangioleiomyomatosis), or lymphatic flow pathologies (termed pulmonary lymphatic perfusions syndrome).23,24

Treatment of a chylothorax usually includes drainage of the fluid (when amount leads to clinical symptoms), therapy of the underlying disease (if possible), and an initial conservative treatment attempt. Conservative therapy aims at reducing lymphatic flow within the vessels to the point that the leakage will spontaneously close up. This can be achieved by either administering a medium chain triglyceride diet,23,78,79 by total parenteral nutrition,80 or an additional administration of somatostatin or octreotid.79,81

When conservative therapy fails, surgical or interventional-radiological treatment options can be considered.82,83 The duration of conservative treatment is under debate.84–86 An active approach of experienced centers is to perform interventional-radiological treatment of chylous drainage over 300 mL within a week after initial diagnosis. However, immediate conversion to surgical or interventional-radiological treatment is highly recommended under the following circumstances:

  • 5 or more days of drainage greater than 300 to 1000 mL,
  • more than 2 weeks of low drainage rates (100–200 mL),
  • unchanged drainage over 2 weeks, and
  • developing malnutrition or metabolic complications of chylous fluid loss.

There are multiple possible surgical approaches to chylothorax23,78,86–90 of which nowadays surgical ligation of the thoracic duct and pleurodesis or a combination of both are of practical relevance.24,91–93 The basic problem of thoracic duct ligation is identifying the thoracic duct and its often occurring anatomical variations.

In the late 1990s, interventional-radiological treatment of chylothorax has been described82 as a viable alternative to surgery. As already discussed, it has long been known that a chylothorax can spontaneously cease after conventional lymphangiography with Lipiodol (usually in combination with conservative treatment).27,29,94 It has been suggested that the leaking oily contrast agent either directly blocks the leakage site or that secondary inflammatory reactions lead to sealing of the leakage by scar tissue. This effect, however, can take weeks and success cannot be foreseen on an individual patient basis. This is why conventional (diagnostic) lymphangiography alone should nowadays only be performed as a last resort, when other measures have been unsuccessful or interventional treatment is technically or anatomically not possible. For planning of a primary lymphatic interventional procedure, anatomical mapping of the lymphatic system, and diagnosis of the underlying pathology, we therefore advocate performing preinterventional MRL as a less invasive imaging option of the lymphatic system.26

Today, the interventional mainstay of chylothorax treatment is lymphangiography-guided transabdominal TDE.28,55,82,83,95,96 The procedure falls into 2 parts:

  1. First, lymphangiography with Lipiodol is performed via a transpedal or a transnodal approach as described previously to opacify the lymphatic vessels in the upper abdomen and the thorax (Fig. 11), thereby identifying a possible interventional access site and possibly the underlying pathology. When preinterventional MRL has been performed, already showing anatomical variations and leakage site, puncture of a lymphatic vessel (primarily the cisterna chyli or the lower thoracic duct) can be attempted as soon as they are opacified without waiting for opacification of the entire thoracic lymphatic system.
  2. In the second part of the intervention, a suitable lymphatic vessel is accessed with a fine needle (eg, 22G) via a fluoroscopy-guided, transabdominal approach. Computed tomography–guided and magnetic resonance–guided approaches have also been described.28,55 After successful puncture, a microwire is introduced into the lymphatic vessel (Fig. 12 and Video 2, Supplemental Digital Content 2, http://links.lww.com/RLI/A465, an introduction of a micro guide wire into a lymphatic vessel after transabdominal puncture), and a microcatheter is used to cannulate the leaking vessel, usually the thoracic duct. Subsequent injection of an iodinated hydrosoluble contrast medium can be performed to visualize the anatomy of the downstream lymphatic system as well as demonstrate the lymphatic pathology. Occlusion of the thoracic duct is then usually achieved with a combination of embolization coils and a mixture of Lipiodol/NBCA (Histo-acryl; B. Braun, Melsungen, Germany; Fig. 13). During injection of the glue, anatomical variations have to be taken into account to avoid continued leakage via aberrant lymphatic vessels. Clinically mixture ratios of Lipiodol/NBCA-based glue of 1:1 to 3:1 are most frequently used for standard TDE. Experimental results showed that polymerization times of Lipiodol/NBCA-based glue depend not only on the mixture ratio, but that also the triglyceride concentration of the chylous fluid within the lymphatic vessel has to be taken into account.65
FIGURE 11

FIGURE 11

FIGURE 12

FIGURE 12

FIGURE 13

FIGURE 13

In cases without lymphatic vessels in the upper abdomen/lower thorax suitable for cannulation, there are several alternative interventional approaches:

  • disruption of small retroperitoneal lymphatic vessels by multiple needle punctures,97
  • retrograde thoracic duct cannulation, either via direct retrograde cervical puncture or transvenous retrograde access,55,98–101 and
  • interstitial transnodal embolization.

To date, there are no data from randomized prospective studies comparing different treatments to support a definitive therapeutic strategy of chylothorax. Therapeutic effects furthermore depend on various parameters such as pathogenesis, anatomical conditions, drainage rates, as well as local expertise with different treatment options.

Success rates of conservative treatment alone vary considerably between 16% and 100%.23,78,85,86,92 Conservative treatment seems to be most effective in cases with low drainage output (<500 mL/d), whereas successful conservative treatment in cases with drainage greater than 1000 mL/d is unlikely.

Success rates of surgical thoracic duct ligation overall are reported between 77% and 100%78,80,86,90,93,102,103 with approximately 10% of patients needing several surgeries.23,79 Pleurodesis also results in clinical success between 73% and 100%,104,105 but at the cost of a possible restrictive pulmonary defect. In the subgroup of patients with nontraumatic chylothorax, the success rate of combined conservative and surgical treatment, however, is considerably worse with only 27%.102 As thoracic duct ligation often has to be performed immediately after larger surgical procedures such as esophagectomy in often severely ill patients, morbidity and mortality rates as high as 38.8% and 25% have been reported, respectively.23,103 Due to new less invasive surgical procedures, shorter conservative treatment attempts, and better perioperative management, these rates reduced in recent years (morbidity, 14%; mortality, 1%).78

The therapeutic effect of conventional lymphangiography with Lipiodol alone for thoracic lymphatic leakages varies considerably with success in 7% to 80% of cases27,29,86,94 and cannot be predicted in an individual patient.

After TDE, clinical success is obviously primarily influenced by technical success of the procedure. Technical success rates in larger retrospective series vary between 47% and 90% and reaches 100% in some smaller studies.28,44,55,78,95,96,106 If cannulation of the lymphatic vessel is successful, clinical success of the procedure is very high. Overall clinical success is observed in approximately 70% to 100% of TDE procedures.28,44,55,95,96,107 As with surgical treatment, the clinical success rate of TDE for nontraumatic chylothorax is considerably lower compared with traumatic chylothorax with only 53% (but still higher than success of surgical treatment).106

Success of lymph vessel disruption by multiple needle punctures is reported between 55% and 70%.97,108 However, personal experience with this technique is less convincing.

Complications of radiological-interventional TDE occur in up to 7% of cases overall.23,28,55,95,96 Possible complications are, for example, systemic/pulmonary embolization of Lipiodol/glue, bleeding, or allergic reactions to the contrast agent. Severe clinical complications such as biliary leakages or severe bleeding necessitating further treatment, however, are rare.55 So far, no mortality attributable to TDE has been reported. As with surgical thoracic duct ligation, TDE can lead to leg swelling or diarrhea in up to 7% and 8%, respectively, on long-term follow-up.109

In summary, interventional treatment of chylothorax should be considered as a primary treatment option in high-output chylous leakage and after failed conservative therapy in centers with experience in lymphatic interventions due to lower morbidity and mortality compared with surgical treatment. Interventional TDE is also a viable therapeutic option after unsuccessful surgery. Patients should therefore be referred for treatment to an experienced center.

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PULMONARY LYMPHATIC PERFUSION SYNDROME

Lymphatic flow in the thorax is usually directed from the abdomen and the lung in the direction of the thoracic duct toward the venous angle. In pulmonary lymphatic perfusion syndrome, lymph flow is pathologically directed via aberrant lymph vessels away from the thoracic duct (or other large lymphatic vessels) into the mediastinum and following the bronchi into the lung parenchyma. This phenomenon can readily be evaluated with conventional Lipiodol or dynamic MRL. It is the pathophysiological underpinning for congenital chylothorax (in newborns), idiopathic chylothorax (in older children and adults), as well as plastic bronchitis (in children and adults). Patients can develop symptoms already after minimal trauma (eg, coughing) or infections. In children, chylothorax or plastic bronchitis is especially observed in patients with congenital heart diseases after Fontan surgery.110 Interventional procedures as described previously are increasingly used in pulmonary lymphatic perfusion syndrome with promising results.111,112

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ABDOMINAL LYMPHATIC INTERVENTIONS INCLUDING HEPATIC LYMPHANGIOGRAPHY AND EMBOLIZATION

Recently, indications for lymphatic intervention have dramatically expanded and today, not only thoracic but also abdominal and pelvic lymphatic pathologies can be managed with interventional, image-guided techniques. Most common abdominal indications include refractory chylous ascites and protein-losing enteropathy.

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INTERVENTIONAL MANAGEMENT OF REFRACTORY CHYLOUS ASCITES

Chylous ascites is defined as the pathological accumulation of a substantial amount of fluid with a milky appearance in the peritoneal cavity requiring a drainage of 1000 mL/d or more for more than 5 days or persistent drainage lasting more than 2 weeks despite conservative treatment.54 The underlying etiology might be a congenital, inflammatory,113 iatrogenic,114,115 or oncologic116 disorder associated with injured and leaking lymphatic vessels. Biochemical analysis of the chylous fluid reveals high concentration of triglyceride levels (200 mg/dL or more).117 Conservative treatment includes high-protein, low-fat diet with medium-chain triglycerides, or, if required, absolute fasting with total parenteral nutrition and intravenous administration of somatostatin analogues such as octreotide.

Nowadays, ultrasound-guided INL has replaced conventional bipedal lymphangiography with surgical exposure of lymph vessels in the foot in many institutions as the standard technique for diagnostic lymphangiography. After draping and cutaneous disinfection, a 25-gauge spinal needle is introduced, under ultrasound guidance, into an accessible LN in both groins. Although INL can be performed with gadolinium-based contrast media followed by magnetic resonance imaging of the thoracoabdominal lymphatic structures, intranodal injection of Lipiodol under fluoroscopic guidance has the advantage to either diagnose the lymphatic disorder and to opacify lymphatic structures during percutaneous intervention, including catheterization and embolization of cysterna chyli and/or side branches. In addition, Lipiodol has also the potential to be theranostic for leaks.39,115 Clinical results of the theranostic effect of intralymphatic use of Lipiodol to treat lymphatic leaks show disappearance of the leak in 50% to 80% of cases, with the highest success ratio in chyle leaks less than 1000 mL/d.39

The therapeutic working mechanism of Lipiodol for chyle leakage has not yet been clarified; however, several researchers suggest that Lipiodol accumulates adjacent to the leakage point and induce regional inflammatory reactions; in addition, like in cTACE, it may also play a role as an embolic agent within the lymphatic vessels.39,54,114,116 Potential complications of Lipiodol-based lymphangiography are low (<5%) and mainly include pulmonary oil embolism or paradoxical stroke in case of associated right-to-left cardiac shunt. Pulmonary embolism might occur if a too high amount of Lipidol is injected (>20 mL) if lymphaticovenous anastomoses are missed on fluoroscopy during injection. In contrast to puncture-related extravasation of iodinated hydrosoluble contrast media, Lipiodol extravasation into the perinodal soft tissues is not associated with pain or tissue necrosis.

Radiologic plain film findings on serial lymphagiographic images may range from no extravasation in case of low-output leakage to clear extravasation in high-output leakages.39

Additional percutaneous interventions may include direct, transabdominal puncture of the leak or a neighboring LN followed by injection of a 1:1 mixture of Lipiodol and NBCA-based glue.118

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INTERVENTIONAL MANAGEMENT OF PROTEIN-LOSING ENTEROPATHY AND POSTOPERATIVE HEPATIC LYMPHORRHEA

For hepatic lymphangiography and embolization a 27-gauge coaxial micropuncture needle introduced into a 22-gauge Chiba needle is used to puncture dilated hepatic lymphatic ducts, located close to and within the wall of the portal vein. Lymph vessels are opacified through injection of Lipiodol or water-soluble iodized contrast medium.119 Abnormalities can be easily shown by lymphangiographic images, for example, dilated liver lymphatic ducts draining the contrast medium into hepatoduodenal connections and lacteals in the duodenal wall (Fig. 14). Occlusion of these lymphatics can be performed with a mixture of Lipiodol and NBCA-based glue120 or with onyx.121

FIGURE 14

FIGURE 14

Most common indications for transhepatic embolization of hepatic lymphatics include protein-losing enteropathy and postoperative hepatic lymphorrhea. Protein-losing enteropathy is characterized by a severe loss of proteins into the intestinal tract, and clinical symptoms include soft tissue swelling, diarrhea, and ascites. These symptoms are mainly seen in patients with congenital heart disease like Fontan patients. In a small series of 8 patients, Itkin et al120 performed 1 or more sessions of hepatic lymphatic duct embolization and found 3 patients with sustained improvement with normalized albumin levels and disappearance of symptoms; in another 3 patients, improvement was temporary, and in the remaining 2 patients, no improvement was found.

Postoperative hepatic lymphorrhea is much less common and related to a surgical complication of lymphatic nodal dissection in the hepatoduodenal ligament. This may result in a leak from liver lymphatic ducts into the abdominal cavity associated with ascites with high protein concentration, but lower triglyceride concentration as seen in chylous ascites.121

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CONCLUSIONS AND OUTLOOK

It appears that now is a time to capitalize on the “forgotten” knowledge about the lymphatic system gathered in the 19th century. The imaging and interventional methods of the lymphatic system, developed over the last 20 years and described in this review, are the foundation for future development of the field. Ability to see the central lymphatic system and potentially estimate the lymphatic flow using DCE-MRL allows us to discover the lymphatic variants and abnormalities as well as evaluate the effects of the different diseases on the lymphatic system. It will guide the therapeutic approaches and interventional techniques with TDE and interstitial embolization providing the foundation for the development of the array of newest treatment methods.

What are the next steps? The “low-hanging fruit” is to replicate the forgotten therapeutic approaches. Thoracic duct access techniques allow us to reintroduce the lymph flow diversion therapies to treat immune-modulated disorders, treatment of the complications and symptoms in congestive heart failure, and potential harvesting of immune factors for immunotherapy. Liver lymphangiogram and interstitial lymphatic embolization will allow us to further develop the technique of imaging and interventions of the lymphatic protein losing enteropathy and liver cirrhosis and heart failure ascites.

The ability to image the lymphatic system can unravel the mystery of illusive lymphatic disorders, such as lymphatic malformations, central conductive lymphatic disorder, pulmonary lymphagiomatosis, intestinal lymphangiomatosis, lymphatic reflux disorders, and maybe some types of lymphedema. Some of the “unsolved” cases of the interstitial lung diseases and pulmonary alveolar proteinosis can be explained by abnormal pulmonary lymphatic flow, which can be reliably imaged using DCE-MRL.

However, even now, some of the important parts of the lymphatic system such as the kidney, lung, and spleen remain relatively poorly understood. Further research of these systems will open the opportunities to develop new interventional methods and techniques.

We are living in the exciting times of the revival of the interest in the lymphatic system, due to development of new imaging and interventional techniques that allow us to revive the old knowledge about the lymphatic system and develop new treatments.

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Keywords:

Lipiodol; ethiodized oil; lymphangiography; lymphography; thoracic duct embolization

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